The long-term objective of this research proposal is to develop the best strategy for treating human erectile dysfunction by understanding the molecular mechanisms associated with this disease. The main goal of this project is to elucidate the molecular mechanisms of impotence associated with penile nerve injury and aging, using rats as an experimental animal model. The rational for this project is that penile nerve injury and aging may play an important role in impotence and therefore understanding of this process will help in treatment of this disease. This proposal is based on the hypothesis that penile nerve injury and aging associated impotence may be due to alteration in nonadrenergic noncholinergic vasodilator system, nitric oxide synthase, guanylate cyclase and cyclic GMP mediated mechanisms. This hypothesis will be achieved through pursuit of the following specific aims: 1) To investigate the role of penile neural injury and aging on nonadrengergic, noncholinergic vasodilator system which is associated with erectile dysfunction. This objective will be achieved by examining the neuroanatomy of penile nerves by NADPH diaphorase (nitric oxide synthase) using immunohistochemistry, light and electron microscopy. 2) To elucidate the molecular mechanisms associated with nerve injury and aging mediated impotence. This objective will be achieved by determining nitric oxide synthase activity (enzymatic assay), immunohistochemistry), nitric oxide gene expression (Northern blot, RNase protection assay), guanylate cyclase, and cyclic GMP. 3) To investigate the role of nerve growth factor in regeneration of nonadrenergic noncholinergic nerves after neurotomy. This objective will be achieved by denervating cavernous nerves and chronic administration of nerve growth factor by an implanted osmotic pump. The nerve regeneration process will be examined by nitric oxide synthase staining and light and electron microscopy. The accomplishment of these experiments will clearly elucidate the molecular mechanisms of impotence associated with penile nerve injury and aging. This proposal will also investigate the nerve growth factor in regeneration of cavernous nerves which might help in treatment of erectile dysfunction associated with nerve injury.